Glycopeptides have been isolated from cerebral cortex cells that inhibit cell division and protein metabolism when added, at nanogram concentrations, to exponentially growing cells in culture. Similar molecules, antigenically related, have been isolated from both mouse and bovine cerebral cortex. While nontransformed cells are sensitive to the presence of the glycopeptides, malignant cells are either relatively resistant or completely refractory to their inhibitory action. The glycopeptides were shown to originate from the cerebral cell surface and their inhibitory activity is nontoxic and completely measured, during inhibition and upon reversal, by the kinetics of cell division, DNA content, and the mitotic index. This unusual property appears to be a feature of the glycopeptide inhibitors, since several cell lines have been shown to be arrested in G2. Since malignant cells are relatively resistant to the inhibitory action of the glycopeptides, the inhibitors have been used to protect selectively normal cells, mixed in culture with transformed cells, from the cytocidal action of drugs that kill cells in the S phase of the cell cycle. Although sialogangliosides on the cell surface are required to provide cellular sensitivity to the glycopeptide inhibitors, the gangliosides do not act as receptors or co-receptors for the inhibitory molecules. It appears that the presence of the gangliosides (GM1, GM3, or GD1A) alters cell membrane physiology in a manner that allows the target cells to respond to the inhibitory glycopeptides. (A)